Corneal transplantation through eye donation is performed for intractable corneal epithelial disease; however, it has problems of absolute donor shortage and rejection reaction after transplantation. To solve these problems, a therapeutic method using patient's own oral mucosal epithelial cells has been developed. This method involves preparing a cultured corneal epithelioid cell sheet from oral mucosal epithelial cells and transplanting the sheet into the affected eye (Patent Literatures 1 to 3 and Non Patent Literature 1). However, this method has the following problem: the sheet using the oral mucosal epithelium is low in transparency and weak compared to that using the corneal epithelium since the mucosal epithelium does not differentiate into a complete corneal epithelium. Because of a difference in the ability to cause vascularization, the invasion of blood vessel may occur in the naturally blood-vessel-free cornea in some cases, after transplanting the oral mucosal epithelial sheet.
Meanwhile, the regenerative medicine research is underway which attempts to compensate damaged tissue/organ by inducing the differentiation of undifferentiated cells (stem cells). Embryonic stem cells (ES cells) can be differentiated into all cells other than those of the placenta, and thus attention has been given to their differentiation induction into each cell lineage and the identification of a factor determining their differentiation. However, the research and use of the stem cells have many limitations due to ethical problems and there is also a problem of rejection reaction. Thus, ES cells have not yet been clinically applied.
The regenerative medicine using artificial pluripotent stem cells, such as iPS cells, not only has no ethical problem but also can use patient-derived cells as a source to avoid the problem of rejection. However, some iPS cells remain as undifferentiated cells even after differentiation induction, and have a risk of tumorigenic transformation after transplanting. There is also the following problem: the establishment and differentiation induction of iPS cells takes several months or more.
On the other hand, methods are known for inducing nerve cells (Non Patent Literature 2) and myocardial cells (Non Patent Literature 3) from skin fibroblasts by direct reprogramming, in which desired somatic cells are directly induced without being via iPS cells. According to these methods, desired somatic cells can be simply obtained in a short period of time without the risk of tumorigenic transformation resulting from the remaining of undifferentiated cells.